Project Summary: Stopping Bleeding in the Spinal Cord after Injury There are approximately 250,000 people in the U.S. with spinal cord injury (SCI) and over 2 million worldwide. SCI leads to chronic functional deficits and significantly decreased quality of life. The human impact of the injury is enormous and the health care costs associated with the injury are the third highest in the U.S. to The impact of spinal cord injury is devastating to the patients, their families, and the health care system. Spinal cord injury, though, is only one of a group of traumas to the central nervous system (CNS) that includes strokes and traumatic brain injuries. In all of these CNS injuries, hemorrhaging is one of the first steps that occurs in the injury process. This is followed by a secondary injury cascade that causes further damage and includes the influx of inflammatory cells and cytokines that exacerbate injury. We have intravenously administered hemostatic nanoparticles that stop internal bleeding including in the spinal cord after injury. We hypothesize that stopping the bleeding will reduce secondary injury progression, limit inflammation, protect tissue and improve function after spinal cord injury. In this proposal, we will determine the optimal window of time for administering the hemostatic nanoparticles after injury to limit bleeding. We will determine the impact of limiting bleeding on the critical inflammatory cells after injury, particularly neutrophils and the polarization of macrophages to the M1 and M2 phenotypes since these have been shown to be highly altered by injury and most critical to the degenerative versus repair processes. We will then determine the short and long term impacts of limiting bleeding following spinal cord injury on the neural tissue preservation and functional recovery. Together this will give us the basis for a potential therapy as well as a mechanistic understanding of the role of bleeding following spinal cord injury. Ultimately, we will be able to combine this approach with drug therapies we are developing to improve outcomes following SCI. Spinal cord injury is not only a devastating trauma, but it is an excellent model for investigating the role of controlling bleeding on inflammation, neural tissue preservation, and functional recovery. The knowledge we gain from this work will be applicable to the treatment of CNS injuries more broadly including traumatic brain injuries and hemorrhagic strokes. The work proposed here will lead to a new approach to treating SCI and CNS injuries more broadly and has the potential to be a translatable technology that fundamentally alters patient outcomes.